Acute myeloid leukaemia (AML) at EHA 2013

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Published: 25 Jun 2013
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Prof Gert Ossenkoppele - VU University Medical Center, The Netherlands

Acute myeloid leukaemia (AML) is a disease with a very poor long term prognosis. Genetic determination of response to therapy is a hot topic in the management of this and other myeloid malignancies. Epigenetic treatment, such as the hypomethylating agents, have shown efficacy in both AML and myeloid dysplastic syndrome (MDS). The majority of patients with myeloid malignancy are over 60 years of age. In these patients it is important to take into consideration the biologic rather than chronological age when deciding on the best treatment strategy. Epigenetic treatment can be an option in less fit elderly patients. There are new drugs available for the treatment of AML. Minimal residual disease detection can help determine whether or not to transplant patients and to determine appropriate post-remission treatment strategies. Targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, are also being evaluated in clinical trials. Overexpression of FLT3 is one of the key targets in AML. Targeting JAK2 has also been found to be important. Translation research will impact on treatment strategies in individual patients and help determine which of the new drugs are likely to be most appropriate.

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

18th Congress of EHA

Acute myeloid leukaemia (AML) at EHA 2013

Prof Gert Ossenkoppele - VU University Medical Center, The Netherlands

What have you found interesting at EHA?

I am mainly involved in the treatment of myeloid malignancies so acute myeloid leukaemia, myelodysplastic syndromes and chronic myeloid leukaemia. There are a lot of interesting things going around. Genetic determination of all kinds of myeloid malignancy is improving much and with the coming of the next generation sequencing much more genomic alterations become clear. We could have the advantage of this for better understanding the disease but also for determining targets of treatment.

Discuss the role of epigenetics and the prediction of response to therapy in the clinical management of AML.

Epigenetic therapy is already around for a couple of years now in myeloid malignancy, mainly in acute myeloid leukaemia, myelodysplastic syndromes. The main new drugs that are available now for daily uses are hypomethylating agents both of them; one is 5-az and the other is decitabine and they have both shown efficacy in acute myeloid leukaemia as well as in myelodysplastic syndromes. Results are still a little bit premature for acute myeloid leukaemia and they have all shown activity as a single monotherapy but I think the advantage would be to put them into combination with other drugs, for example in combination with chemotherapy or with other immune modulating agents. There are some interesting aspects here. For example, in acute myeloid leukaemia the combination of lenalidomide with azacitidine has been proven very effective, producing high CR rates in very high risk AML patients. The interesting thing is that they also looked at the genetic determinants of response so it was possible to predict the response based on the genetic signature at diagnosis. So that is also interesting that you can, up front, select your patients who will benefit from epigenetic treatment. It’s not all set out currently but it’s work in progress, I think, and that’s a very interesting field of investigation currently.

What are some of the challenges facing you as a clinician when treating elderly patients?

We know that the majority of patients with myeloid malignancies are above the age of 60. We must not forget that the patient who is 60 now is a totally different patient from the patient that was 60 twenty years ago. They are much more fit than twenty years ago so they can have rather intensive treatment. So I think the first choice you have to make as a clinician – is my patient fit enough to receive intensive treatment because treatment results are the best way of receiving intensive treatment. But of course there are a couple of patients, and mainly they are above the age of 70 or 75, that are not fit enough to receive intensive treatment. So we have to define that population, it’s very difficult to define who is fit and unfit for receiving intensive treatment but we have methods for that. But for those who are really unfit to receive therapy, for example, epigenetic treatment which is much less intensive could be of advantage for them. And most of the results that currently are available on epigenetic treatment have been obtained in the elderly population. Sometimes with oral treatment you can give it as outpatients so that is a major advantage for treating those patients.

There are new drugs on the market currently that seem to be effective in AML also orally. For example, a group from Ulm presented a study in which they combined a new drug, a polo kinase 1 inhibitor that’s a signal transduction inhibitor, in combination with low dose cytostatic treatment and they compared it with the cytostatic treatment on its own, so it was a randomised phase II study and they showed a major advantage for the combination of polo kinase 1 and low dose Ara-C in comparison to low dose Ara-C on its own. So that is one of the ways we are moving to combining new signal inhibitors with low intensity treatment for the elderly, unfit patients that cannot achieve intensive treatment.

What is the importance of detecting and treating minimal residual disease in AML patients?

That’s my main topic of research, the minimal residual disease detection, and I’m very much in favour to use that as an on-treatment method to measure the disease. It’s known there are a couple of methods to measure minimal residual disease; one is by flow cytometry looking to see new types that you try to detect at diagnosis and then you can follow during treatment the minimal residual disease in the patient. And we have shown in HOVON in a huge study and a prospective study that when you do that then you can see that after one or two courses when you measure the minimal residual disease load and when it’s very low those patients are doing much better than when there is still minimal residual disease left. So you can make the decision to transplant or not to transplant those patients based on the minimal residual disease load. And also in this congress there was a presentation, again from the Ulm group, who looked at another way of minimal residual disease detection that was measuring the Mpn1 mutation status. Also they showed that when there is, after treatment, a high level of transcripts present then those patients do much worse than those who have a low level of Mpn1 mutation present at that moment. So very important tools to decide what kind of post-remission treatment you will give and offer to your patient, to transplant or not to transplant, it’s a big decision.

What has been learnt from the latest data released for targeted therapies?

I think most data are available on the FLT3-ITD inhibitors and phase I/phase II studies show that in that patient that show that inhibition is present in around 20% of the patients they show efficacy. So these data are available; they have now also presented on this congress data on a huge amount of patients showing a high degree of achieving complete remission in relapsing and refractory FLT3-ITD patients and that was with drug AC220. There is a study on-going in up-front patients which has just closed and we are eagerly waiting for the results on that study. But also a study in refractory and relapsing patients will now start comparing the standard chemotherapy for relapsing or refractory patients, although nobody knows what is the standard treatment for that difficult group of patients.

So most data are available on the FLT3-ITD mutated patients; JAK2 is, of course, of importance also in AML although much attention is now paid to it because it’s highly expressed in some myeloproliferative diseases and there are a lot of JAK2 inhibitors available currently in, for example, myelofibrosis. And we first thought that it did not change the biology of the disease but it was very important for patients because they have sometimes very bad symptoms of the disease and they disappear very quickly after treatment with a JAK2 inhibitor. But it seems now data are more mature that it also changes a little bit the biology of this disease and maybe improves overall survival and diminishes the fibrosis in the bone marrow. So also JAK2 is a very important drug and it could be also useful in acute myeloid leukaemia although there are no data currently available on that. I think we have to start studies in acute myeloid leukaemia.

How will this research impact on everyday clinical practice?

One example of good translational research is the implementation now of the minimal residual disease detection because that can change the strategy in the individual patient. But we have to look to new drugs because we failed to improve the outcome for the AML patients in the last 20-30 years. There are now a lot of new drugs available so it’s very difficult to choose which one you want to investigate, there are more new drugs than patients, I should say. So we have to look to new trial designs, not the huge 3,000 numbered patient trials but just short phase II trials with maybe a kind of surrogate endpoint, and then again minimal residual disease could serve as a surrogate endpoint, to decide which drug has the most promise. Also the availability of new monoclonal antibodies, as in acute lymphatic leukaemia, has been proven, blinatumomab has been proven, a very effective bispecific antibody. These antibodies are now also in the development phase for acute myeloid leukaemia so also there is much promise and I think we will see improvement in the upcoming years by implementing all those new drugs via intelligent trial design into the clinical practice.